Research increasingly shows the links between frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS), both devastating neurodegenerative diseases. FTD, ALS, and their overlap subtypes can be difficult to differentiate from other neurodegenerative disorders and from each other, particularly early in their course. Furthermore, there is very little data that would enable the monitoring of progression. Improving our capacity to diagnose and monitor progression would be not only extremely useful for treatment development, but also very valuable for improving our understanding of the basic systems biology of these disorders. This project aims to better define the functional and structural measures of frontal and motor systems of the brain in order to determine whether this knowledge can be used to diagnose and monitor the progression of these disorders. The principal investigator of this proposal is a behavioral neurologist who directs the FTD Unit at MGH, a multidisciplinary clinical-research program with a cohort of more than 100 patients. A growing number of patients are being identified with elements of both FTD and ALS. The Co-PI is a systems neuroanatomist who has worked for many years to develop and apply quantitative neuroimaging methods to characterize and measure the topography of large-scale brain networks, and to apply this knowledge to neurologic and psychiatric disorders. We have collected preliminary data indicating that FTD and ALS affect specific nodes of partially overlapping brain networks. We propose here to use advanced imaging techniques to refine knowledge of the functional and structural connectivity of these networks in patients on the FTD-ALS spectrum. In addition to adding to our fundamental knowledge of brain networks, this work has the potential to lay a framework for the development of tools for diagnosis and monitoring of FTD-ALS, which we hope will be useful for the testing of new therapeutic interventions in these devastating neurologic disorders.